Enhanced Fibrinolytic Potential in Mice with Combined Homozygous Deficiency of α2-antiplasmin and PAI-1

M. Dewerchin; D. Collen; H. R. Lijnen

doi:10.1055/s-0037-1616099

Thrombosis and Haemostasis, Inhaltsverzeichnis

Thromb Haemost 2001; 86(02): 640-646
DOI: 10.1055/s-0037-1616099

Review Article

Schattauer GmbH

Enhanced Fibrinolytic Potential in Mice with Combined Homozygous Deficiency of α₂-antiplasmin and PAI-1

Autor*innen

M. Dewerchin

¹Center for Transgene Technology and Gene Therapy, Flanders Interuniversity Institute for Biotechnology, Leuven, Belgium
D. Collen

¹Center for Transgene Technology and Gene Therapy, Flanders Interuniversity Institute for Biotechnology, Leuven, Belgium

²Center for Molecular and Vascular Biology, University of Leuven, Belgium
H. R. Lijnen

²Center for Molecular and Vascular Biology, University of Leuven, Belgium

Abstract

Summary

α₂-antiplasmin (α₂-AP) and plasminogen activator inhibitor-1 (PAI-1) are the main physiological inhibitors of the plasminogen/ plasmin system in mammalian plasma. In the present study, the relative importance of both inhibitors was evaluated with the use of mice with single or combined deficiency of α₂-AP and PAI-1 in the same genetic background. Mice with combined deficiency (α₂-AP^–/–:PAI-1^–/–) are viable, develop normally and are fertile. After amputation of the tail, bleeding times are prolonged (>15 min) in α₂-AP^–/–:PAI-1^–/– mice, as compared to double wild-type or single deficient mice (4.6 to 10 min). Spontaneous lysis after 4 h of intravenously injected ¹²⁵I-fibrin labeled plasma clots is significantly higher in mice with α₂-AP deficiency both in the PAI-1^+/+ background (89 ± 2% versus 42 ± 3%; p = 0.002) and in the PAI-1^–/– background (83 ± 4% versus 53 ± 5%; p = 0.002). PAI-1 deletion in the α₂-AP^+/+ or α₂-AP^–/– background, however, has no significant effect (p = 0.13 or 0.18, respectively). Four hours after endotoxin injection, fibrin deposition in the kidneys is not significantly affected by PAI-1 deletion in mice with α₂-AP^+/+ or α₂-AP^–/– background (p = 0.07 and 0.19, respectively). In contrast, α₂-AP deletion causes significantly reduced fibrin deposition in the PAI-1^+/+ background (p = 0.01). Endotoxin injection causes a dramatic increase in PAI-1 antigen levels in kidney extracts of PAI-1^+/+ animals, without effect on α₂-AP levels.

Taken together, these data indicate that the higher endogenous fibrinolytic capacity observed in mice with combined deficiency is mainly due to the lack of α₂-AP and suggest a less important role for PAI-1.

Keywords

α₂-antiplasmin - plasminogen activator inhibitor-1 - gene targeting - fibrinolysis

Volltext

Referenzen

References
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